The invention described herein relates to compounds for the preparation of medicaments useful for the treatment of psychiatric and neurological disorders, to processes for their preparation and to pharmaceutical compositions containing them as active ingredients. In particular, the invention described herein relates to compounds with a pyrrolobenzothiazepine structure with typical and a typical antipsychotic activity that can be formulated in pharmaceutical compositions intended for the treatment of acute and chronic psychotic states.
The involvement of dopamine and of the dopaminergic neurons in a variety of psychiatric and neurological disorders, has now been extensively documented (E. R. Kandel, J. H. Schwartz, in xe2x80x9cPrinciples of Neural Sciencexe2x80x9d Neurologyxe2x80x9d, Elsevier Science Publishing Co. New York, 1985).
Among the various pathologies concerned, schizophrenia is characterised by a complex symptomatology caused by abnormal neurotransmission of the main dopaminergic pathways of the central nervous system. The states of hallucination and deliria, described as positive symptoms, are due to increased activity of the mesolimbic dopaminergic pathway, while the cognitive deficits and states of social isolation, indicated as negative symptoms, are attributed to reduced dopaminergic neurotransmission in the frontal cortex.
The condition of hyperactivation of dopaminergic neurotransmission which underlies the acute and chronic psychotic states of schizophrenia, acute psychoses of unknown aetiology, and the forms of psychosis and agitation that form part of the symptomatology of other diseases, is counteracted from a therapeutic point of view by the use of classic antipsychotic agents, otherwise called neuroleptics, the most representative of which are chlorpromazine (phenothiazine class) and haloperidol (butyrophenone class).
Chlorpromazine was the first product to prove distinctly effective in the treatment of psychoses. This compound, initially used as a sedative, proved capable of improving the condition of psychotic patients, in that it was capable of inducing a particular indifference to environmental stimuli without altering the state of vigilance of the subjects using it. Thanks to the enormous commercial success of chlorpromazine, a search began in the ""50s for new neuroleptic agents and this soon led to the identification of other antipsychotic products belonging to many chemical classes.
The therapeutic efficacy of the neuroleptics is related to their ability to modulate the dopaminergic neurotransmission of the central nervous system, via blockade of the dopamine receptors.
Their antipsychotic potency is directly proportional to their ability to bind and block dopamine receptors of subtype D2 in the cerebral areas involved in abnormal functional dopaminergic neurotransmission. Moreover, psychopharmacology studies show that the dopaminergic hyperactivity that affects the mesolimbic pathway also involves the receptor subtypes D1 and D3. Consequently, the antipsychotic potency of a neuroleptic may also depend on its ability to interact with these receptors, which are densely distributed on the neuronal endings in this pathway (J. Schwartz, Giro B., M. P. Martres and P. Sokoloff xe2x80x9cNeurosciencexe2x80x9d 4, 99-108; 1992).
From the clinical point of view, the antipsychotic efficacy of the numerous neuroleptic agents present on the market is qualitatively equivalent in all cases. They differ only in their potency, in the sense that, whereas some of them are effective at doses of only a few mg, others need to be administered at much higher doses.
The real differences between the various neuroleptic agents depend on their ability to favour the occurrence of unwanted side effects such as arterial hypotension, sedation and, above all, severe motor abnormalities, some of which are among the most frequent manifestations associated with the clinical efficacy of the treatment. Whereas the former are due to the ability of the product to interact with the alpha-1 adrenergic and H1 histaminergic receptors, respectively, the latter, common to all neuroleptic agents, are due to blockade of the D2 receptors of the nigrostriatal dopaminergic system.
Pharmacological and clinical studies have shown that the simultaneous administration of neuroleptics and products with selective antagonist activity on serotoninergic 5-HT2a receptors can increase the antipsychotic efficacy of the former and attenuate the occurrence of extrapyramidal symptoms as compared to treatment with neuroleptic agents alone (G. F. Busatto and R. W. Kerwin xe2x80x9cJournal of Psychopharmacologyxe2x80x9d 11(1), 3-12; 1997).
Further developments in this sense have led to the generation of drugs with a mixed antagonist component, i.e. which are active on different receptors.
Clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is an antipsychotic agent capable of simultaneously antagonising dopamine on D2 receptors and serotonin on 5-HT2 receptors. This new action profile, called xe2x80x9catypicalxe2x80x9d, allows schizophrenia to be treated with a lower incidence of extrapyramidal symptoms (J. Med. Chem., 39, 1996, pp. 1172-1188).
Unfortunately, the occurrence of cases of agranulocytosis has limited the therapeutic use of this drug (Lancet. 1975, 2, 657).
Octoclothepine (8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepine) is a compound partly endowed with xe2x80x9catypicalxe2x80x9d activity. Its pharmacological activity has been studied in relation to the optical isomers of this compound (J. Med. Chem., 1991, 34, 2023-2030): a slightly greater effect on schizophrenia by the (S) form is unfortunately associated with a greater incidence of extrapyramidal effects, so that its use has been withdrawn from clinical trials. The (R) isomer presents a more xe2x80x9catypicalxe2x80x9d profile, with fewer side effects, but also an inferior general potency. Moreover, the two isomers prove to be endowed with the same activity as 5-HT2 and D1 antagonists.
In view of the studies cited above, the need for antipsychotic agents with substantial therapeutic activity and without side effects remains unsatisfied. In particular, the search continues for antipsychotic agents which present greater neuroleptic activity, a lower incidence of extrapyramidal effects and minimal side effects (agranulocytosis; neutropaenia; sedation; weigh gain; costipation; urinary retention; dryness; hypotension).
It has now been found that compounds of the 9-amino-substituted pyrrolo[2,1-b][1,3]benzothiazepine class, particularly formula (I) compounds 
where:
R=H, Cl, Br, F, I, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, C5-C6 cycloalkyl;
R1=C1-C4 dialkylamine, where the alkyl groups can be the same or different from one another, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl, 4-alkyl-1-homopiperazinyl;
R2=H, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, CHO, CHxe2x95x90NOH;
R3=H, CHO;
are endowed with antipsychotic activity.
One object of the invention described herein therefore consists in the formula (I) compounds indicated here above and their pharmaceutically acceptable salts.
Another object of the invention described herein consists in processes for the preparation of formula (I) compounds.
A further object of the invention described herein is the use of said compounds as medicaments useful as antipsychotic agents for the treatment of psychiatric and neurological disorders, particularly disorders related to increased activity of the mesolimbic dopaminergic pathway and/or mesocortical dopaminergic hypofunction such as schizophrenia in its positive and negative symptoms.
Still another object of the present invention is the use of said compounds as medicaments, in particular as antipsychotic agents, for the treatment of psychosis, such as schizophrenia, paranoid states, manic-depressive states, affective disorders, social withdrawal, personality regression, hallucinations or cognitive dysfunctions.
Yet another object of the invention described herein consists in pharmaceutical compositions containing a formula (I) compound in a mixture with at least one pharmaceutically acceptable vehicle and/or excipient.
In the formula (I) compounds, what is meant by the terms C1-C4 are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and ter-butyl.
Among the formula (I) compounds, a first preferred group includes those in which R1 is 4-alkyl-1-piperazinyl. A second preferred group includes those in which R is H, Cl, Br, F, I.
In particular, when R=Cl, R1=4-metil-piperazin, R3=H, R2=H the compounds are typical antipsychotics, while for R=H,F; R2=H, CHO, CH3; R3=H; R1=4-methyl-1-piperazinyl, the compounds are a typical antipsychotics.
Among typical antipsychotics, one particularly preferred compound is 7-chloro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine (hereinafter also referred to as ST1508), particularly the maleate (hereinafter also referred to as ST1699).
Preferred compounds of formula (I) with antipsychotic a typical activity, according to the invention are:
9-(4-methyl-1-piperazinyl) pyrrolo[2,1-b][1,3]benzothiazepine (ST1899);
7-fluoro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine (ST1928)
1-Methyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine (ST2092).
The compounds according to the invention described herein are prepared starting from the formula (Ia) compound 
where R and R2 are as defined above for the formula (I) compound, which is reacted with the desired amine R1H as defined for the R1 group to yield the formula (I) compounds.
The preparation of the formula (Ia) compound is described in patent application WO 00/06579, filed in the name of the applicant.
The transformation from compound (Ia) into compound (I) is effected with known techniques, but it has been seen that the reaction is conveniently achieved by treating compound (Ia) with amine R1H in the presence of Lewis acids, e.g. triflates, such as trimethylsilyltrifluoromethane sulphonate, or protic acids, such as sulphonic acids, e.g. p-toluene sulphonic acid.
The reaction is conducted in a solvent inert to the reagents and the reaction products, or, preferably, amine R1H can be used in relation to compound (Ia) in an excess such as to constitute the reaction medium. The reaction parameters are not critical and can be determined by a technician with average experience in the field on the basis of his or her own general knowledge of the subject. For example, the molar ratios of compound (Ia) to amine R1H may range from 1:1 to an excess of amine in the sense referred to above. The reaction temperature will be selected also in relation to the type of reagents used, their molar ratios, and the optional presence of a solvent, in which case it may even be as high as the boiling temperature of the solvent, providing this does not lead to decomposition of the reagents themselves. The reaction times are selected on the basis of the parameters outlined above and will be such as to complete the reaction. Attempts to optimise the reaction do not constitute an additional experimental burden and are part of the normal techniques used in chemical synthesis.
The isolation and purification of the formula (I) compound are accomplished with normal known procedures.
In a first preferred embodiment of the invention, the formula (Ia) compound is reacted with amine R1H, using the latter as a reaction medium, when its physicochemical characteristics so permit. The triflate preferred is trimethylsilyltrifluoromethane sulphonate. The reaction temperature is approximately 120xc2x0 C. and the reaction time approximately 3 hours.
In a second preferred embodiment of the invention, the formula (Ia) compound is reacted with amine R1H, using the latter as the reaction medium, when its physicochemical characteristics so permit. The preferred sulphonic acid is p-toluene sulphonic acid. The reaction temperature is approximately 180xc2x0 C. and the reaction time approximately 1-2 hours.
Objects of the invention described herein are pharmaceutical compositions containing as their active ingredient at least one formula (I) compound, alone or in combination with one or more formula (I) compounds, or, said formula (I) compound or compounds in combination with other active ingredients useful in the treatment of the diseases indicated in the invention described herein, for example, other products with selective antagonist activity on the serotoninergic 5-HT2a receptors, also in separate dosage forms or in forms suitable for combined therapy. The active ingredient according to the invention described herein will be in a mixture with suitable vehicles and/or excipients commonly used in pharmacy, such as, for example, those described in xe2x80x9cRemington""s Pharmaceutical Sciences Handbookxe2x80x9d, latest edition. The compositions according to the invention will contain a therapeutically effective amount of the active ingredient. The doses will be determined by an expert in the field, e.g. clinician or primary care physician, according to the type of disease to be treated and the patient""s condition, or concomitantly with the administration of other active ingredients. By way of an example, we may indicate doses ranging from 0.1 to 100 mg/kg.
Examples of pharmaceutical compositions are those that permit oral, parenteral, intravenous, intramuscular, subcutaneous or transdermal administration. Pharmaceutical compositions suitable for the purpose are tablets, rigid or soft capsules, powders, solutions, suspensions, syrups, and solid forms for extempore liquid preparations. Compositions for parenteral administration are, for example, all the intramuscular, intravenous and subcutaneous injectable forms, and those in the form of solutions, suspensions, and emulsions. We should also mention the forms presenting controlled release of the active ingredient, whether as oral administration forms, tablets coated with suitable layers, microencapsulated powders, complexes with cyclodextrins, depot forms, e.g. subcutaneous ones, as depot injections or implants.
The following examples further illustrate the invention.